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MCF-7
Terms modified by MCF-7 Selected Abstracts[Tris(pyrazolyl)methane]ruthenium Complexes Capable of Inhibiting Cancer Cell GrowthEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 31 2009Jesse M. Walker Abstract The [tris(pyrazolyl)methane]ruthenium complexes [(,3 -tpm)RuCl(solv)2]PF6 [tpm = tris(pyrazolyl)methane; solv = MeCN, dmso] and [(,3 -tpm)RuCl(LL)]PF6 [LL = ,2 -dppe, ,2 -dppp, ,2 -dppb, (PMePh2)2] have been prepared, characterized and screened in vitro for their antiproliferative properties against the MCF-7 (breast) and HeLa (cervical) cancer cell lines by using the MTT assay. Although the MeCN and dmso complexes showed no activity under the conditions used, the phosphane complexes exhibited remarkable cytotoxic behaviour. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source] Cytotoxic Rhodium(III) Polypyridyl Complexes Containing the Tris(pyrazolyl)methane Coligand: Synthesis, DNA Binding Properties and Structure,Activity RelationshipsEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 25 2009Ruth Bieda Abstract The RhIII complexes of the type [RhCl(pp)(tpm)]2+ [pp = bpy, bpm, phen, tap, dpq, dppz] 4,9 have been prepared by stepwise treatment of RhCl3·3H2O or mer,cis -[RhCl3(DMSO-,S)2(DMSO-,O)] with the appropriate polypyridyl ligand (pp) followed by the tripodal ligand tris(pyrazolyl)methane (tpm). Intermediates of the type [RhCl3(CH3OH)(pp)] 1,3 with pp = bpy, phen, dpq were also characterized but exhibit either low (3) or no (1, 2) cytotoxicity. X-ray structural analyses of [RhCl(bpy)(tpm)][PF6]24 and [RhCl(phen)(tpm)][PF6]26 were performed, and the interaction of complexes 4,9 with DNA was investigated by CD and UV/Vis spectroscopy and by gel electrophoresis. CD and viscosity studies confirm strong intercalation of dppz complex 9 into DNA. Complexes 8 and particularly 9 (IC50 = 0.43, 0.37 ,M) are potent cytotoxic agents towards the human cancer cell lines MCF-7 and HT-29, whereas respectively little (complex 6) or no activity (complexes 4, 5, 7) is observed for the other members of the series. Our findings indicate that the cytotoxicity is dependent on the hydrophobicity of both the polypyridyl and the facial coligand in these and other half-sandwich RhIII complexes. Irradiation of bpy compound 4 in the presence of plasmid pBR322 for 30 min at 311 nm at a molar ratio of r = 0.1 leads to total conversion of the supercoiled form into the nicked version. Although dppz complex 9 also functions as a photonuclease under these conditions, the degree of cleavage is much lower. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source] Characterization by NMR Spectroscopy, X-ray Analysis and Cytotoxic Activity of the Ruthenium(II) Compounds [RuL3](PF6)2(L = 2-Phenylazopyridine or o -Tolylazopyridine) and [RuL'2L"](PF6)2(L', L" = 2-Phenylazopyridine, 2,2'-Bipyridine)EUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 13 2005Anna C. G. Hotze Abstract Tris(ligand) complexes [RuL3](PF6)2 (L = 2-phenylazopyridine or o -tolylazopyridine) and mixed ligand [RuL'2L"](PF6)2 (L' and L" are 2-phenylazopyridine or 2,2'-bipyridine) have been synthesized, structurally characterized and investigated for cytotoxic activity. These complexes are important to study the hypothesis that the compound ,-[Ru(azpy)2Cl2] (azpy = 2-phenylazopyridine) exhibits a high cytotoxicity due to its two cis chloride ligands, which might be exchanged for biological targets as DNA. Molecular structures of mer -[Ru(azpy)3](PF6)2 (1) and mer -[Ru(tazpy)3](PF6)2 (5) (tazpy = o -tolylazopyridine) have been determined by X-ray diffraction. Series of complexes [RuL3](PF6)2 and [RuL'2L"](PF6)2 show interesting NMR spectroscopic data; e.g. the spectrum of mer -[Ru(azpy)3](PF6)2 (1) shows extremely broadened resonances at room temp. but sharpened resonances at low temperature. In the 1H NMR spectra of compounds [Ru(azpy)2(bpy)]2+ and [Ru(bpy)2(azpy)]2+ (bpy = 2,2-bipyridine), respectively, less broadened (room temp.) or completely sharp resonances (room temp.) occur in comparison to 1 (under same conditions). By selecting the right temperature and/or concentration, NMR spectra of these series of compounds have been resolved using 2D COSY and NOESY NMR spectroscopy. Remarkably, the cytotoxicity data against a series of human tumor cell lines (A498, EVSA-T, H226, IGROV, M19, MCF-7 and WIDR) show a moderate cytotoxicity for these series of tris(ligand) complexes. So, even though no chloride ligands are present in these tris(ligand) complexes, a considerable cytotoxic activity is observed. This would imply that the 2-phenylazopyridine ruthenium(II) complexes act by a completely different mechanism than the well-known cisplatin. This finding is important, because an anticancer compound acting via a different mechanism is a prerequisite in designing new anticancer drugs. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Trichocladinols A,C, Cytotoxic Metabolites from a Cordyceps -Colonizing Ascomycete Trichocladium opacumEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 32 2009Huijuan Guo Abstract Trichocladinols A,C (1,3), three new metabolites, and the known massarigenin A (4), have been isolated from cultures of a Cordyceps -colonizing ascomycete Trichocladium opacum. Their structures were elucidated by NMR spectroscopy and X-ray crystallography. The absolute configuration of 1 was assigned by using the modified Mosher method and that of 3 was determined by X-ray crystallographic analysis of its (S)-MTPA ester. Compounds 1,3 showed modest cytotoxic effects against the human tumor cell lines HeLa and MCF-7. Structurally, compounds 1 and 2 possess a previously undescribed 2,9-dioxatricyclo[5.2.1.03,8]dec-4-ene skeleton.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009) [source] Self-Assembling Peptide as a Potential Carrier for Hydrophobic Anticancer Drug Ellipticine: Complexation, Release and In Vitro DeliveryADVANCED FUNCTIONAL MATERIALS, Issue 1 2009Shan Yu Fung Abstract The self-assembling peptide EAK16-II is capable of stabilizing hydrophobic compounds to form microcrystal suspensions in aqueous solution. Here, the ability of this peptide to stabilize the hydrophobic anticancer agent ellipticine is investigated. The formation of peptide-ellipticine suspensions is monitored with time until equilibrium is reached. The equilibration time is found to be dependent on the peptide concentration. When the peptide concentration is close to its critical aggregation concentration, the equilibration time is minimal at 5,h. With different combinations of EAK16-II and ellipticine concentrations, two molecular states (protonated or cyrstalline) of ellipticine could be stabilized. These different states of ellipticine significantly affect the release kinetics of ellipticine from the peptide-ellipticine complex into the egg phosphatidylcholine vesicles, which are used to mimic cell membranes. The transfer rate of protonated ellipticine from the complex to the vesicles is much faster than that of crystalline ellipticine. This observation may also be related to the size of the resulting complexes as revealed from the scanning electron micrographs. In addition, the complexes with protonated ellipticine are found to have a better anticancer activity against two cancer cell lines, A549 and MCF-7. This work forms the basis for studies of the peptide-ellipticine suspensions in vitro and in vivo leading to future development of self-assembling peptide-based delivery of hydrophobic anticancer drugs. [source] New Briaranes from the South China Sea Gorgonian Junceella fragilisHELVETICA CHIMICA ACTA, Issue 8 2005Shu-Hua Qi Three new briarane diterpenes, junceellonoids C,E (1,3), along with six known briaranes, junceellin A (4), praelolide (5), and junceellolides A-D (6,9), were isolated from the EtOH/CH2Cl2 extracts of the South China Sea gorgonian coral Junceella fragilis. The structures of 1,3 were established by extensive spectroscopic analysis, including 1D- and 2D-NMR data. Compounds 1 and 2 exhibited mild cytotoxicity against human galactophore carcinoma (MDA-mB-231 and MCF-7) cells at the concentration of 100,,M. [source] Insulin Secretagogues from Moringa oleifera with Cyclooxygenase Enzyme and Lipid Peroxidation Inhibitory ActivitiesHELVETICA CHIMICA ACTA, Issue 2 2004Jayaraj Bioassay-directed isolation and purification of the methanol extract of Moringa oleifera fruits yielded bioactive N -benzyl thiocarbamates, N -benzyl carbamates, benzyl nitriles, and a benzyl ester. Among these, methyl 2-[4-(, - L -rhamnopyranosyl)phenyl]acetate (2), N -[4-(, - L -rhamnopyranosyl)benzyl]-1- O - , - D -glucopyranosylthiocarboxamide (3), 1- O -phenyl- , - L -rhamnopyranoside (5), and 4-[(, - D -glucopyranosyl)-(1,3)-(, - L -rhamnopyranosyl)]phenylacetonitrile (6) are novel, and their structures were determined by spectroscopic methods. The known compounds isolated and characterized from the MeOH extract were niazirin (=4-(, - L -rhamnopyranosyl)phenylacetonitrile; 1), niazicin A (=methyl N -{4-[(4,- O -acetyl- , - L -rhamnopyranosyl)benzyl]}thiocarbamate; 4), methyl N -{4-[(, - L -rhamnopyranosyl)benzyl]}carbamate (7), and methyl N -{4-[(4,- O -acetyl- , - L -rhamnopyranosyl)benzyl]}carbamate (8). The combined yield of these compounds from dried M. oleifera fruits was 1.63%. In rodent pancreatic , -cells (INS-1), compounds 4, 5, 6, 7, and 8 at 100,ppm significantly stimulated insulin release. Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibition assays revealed that 5 and 6 were most active at 83,ppm. Compound 6, however, demonstrated greater specificity for inhibition of COX-2 enzyme (46%) than COX-1 enzyme. Lipid peroxidation assays revealed that 4 and 6 at 50,ppm inhibited peroxidation reactions by 80 and 95%, respectively, while 3 and 8 inhibited lipid peroxidation by 35%. These compounds did not inhibit the cell growth when tested with human breast (MCF-7), central nervous system (CNS, SF-268), lung (NCI-H460), or colon (HCT-116) cancer cell lines. Moreover, these compounds were not cytotoxic at the concentrations tested. [source] Allelic imbalance (AI) identifies novel tissue-specific cis- regulatory variation for human UGT2B15,HUMAN MUTATION, Issue 1 2010Chang Sun Abstract Allelic imbalance (AI) is a powerful tool to identify cis -regulatory variation for gene expression. UGT2B15 is an important enzyme involved in the metabolism of multiple endobiotics and xenobiotics. In this study, we measured the relative expression of two alleles at this gene by using SNP rs1902023:G>T. An excess of the G over the T allele was consistently observed in liver (P<0.001), but not in breast (P=0.06) samples, suggesting that SNPs in strong linkage disequilibrium with G253T regulate UGT2B15 expression in liver. Seven such SNPs were identified by resequencing the promoter and exon 1, which define two distinct haplotypes. Reporter gene assays confirmed that one haplotype displayed ,20% higher promoter activity compared to the other major haplotype in liver HepG2 (P<0.001), but not in breast MCF-7 (P=0.540) cells. Reporter gene assays with additional constructs pointed to rs34010522:G>T and rs35513228:C>T as the cis -regulatory variants; both SNPs were also evaluated in LNCaP and Caco-2 cells. By ChIP, we showed that the transcription factor Nrf2 binds to the region spanning rs34010522:G>T in all four cell lines. Our results provide a good example for how AI can be used to identify cis -regulatory variation and gain insights into the tissue specific regulation of gene expression. Hum Mutat 30:1,9, 2009. © 2009 Wiley-Liss, Inc. [source] BRCA1 modulates malignant cell behavior, the expression of survivin and chemosensitivity in human breast cancer cells,INTERNATIONAL JOURNAL OF CANCER, Issue 12 2009Moltira Promkan Abstract BRCA1 is a multifunctional tumor-suppressive protein. Many functional aspects of BRCA1 are not fully understood. We used a shRNA approach to probe the function of BRCA1 in human breast cancer cells. Knocking down BRCA1 expression by shRNA in the wild-type BRCA1 human breast cancer MCF-7 and MDA-MB-231 cells resulted in an increase in cell proliferation, anchorage-independent growth, cell migration, invasion and a loss of p21/Waf1 and p27Kip1 expression. In BRCA1 knocked-down cells, the expression of survivin was significantly up regulated with a concurrent decrease in cellular sensitivity to paclitaxel. We also found that cells harboring endogenous mutant or defective BRCA1 (MDA-MB-436 and HCC1937) were highly proliferative and expressed a relatively low level of p21/Waf1 and p27Kip1 by comparison to wild-type BRCA1 cells. Cells harboring mutated BRCA1 also expressed a high level of survivin and were relatively resistant to paclitaxel by comparison to wild-type cells. Increase resistance to paclitaxel was due to an increase in the expression of survivin in both the BRCA1 knocked-down and mutant BRCA1 cells because knocking down survivin expression by siRNA restored sensitivity to paclitaxel. We conclude that BRCA1 down-modulates the malignant behavior of breast cancer cells, promotes the expression of p21/Waf1, p27Kip1 and inhibits the expression of survivin. Moreover, loss of BRCA1 expression or function leads to an increase in survivin expression and a reduction in chemosensitivity to paclitaxel. © 2009 UICC [source] Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphateINTERNATIONAL JOURNAL OF CANCER, Issue 9 2008Yoshinori Okamoto Abstract Raloxifene (RAL) significantly reduced the incidence of breast cancer in women at high risk of developing the disease. Unlike tamoxifen (TAM), an increased incidence of endometrial cancer was not observed in women treated with RAL. However, RAL, having two hydroxyl moieties, can be conjugated rapidly through phase II metabolism and excreted, making it difficult to achieve adequate bioavailability by oral administration in humans. As a result, higher doses must be administered to obtain an efficacy equivalent to that achieved with TAM. To improve oral bioavailability and antitumor potential, RAL diphosphate was prepared as a prodrug. RAL diphosphate showed several orders of magnitude lower binding potential to both ER, and ER, and weak antiproliferative potency on cultured human MCF-7 and ZR-75-1 breast cancer cells, as compared to RAL. However, RAL diphosphate has a much higher bioavailability than RAL, endowing it with higher antitumor potential than RAL against both 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats and human MCF-7 breast cancer implanted in athymic nude mice. The RAL prodrug may provide greater clinical benefit for breast cancer therapy and prevention. © 2008 Wiley-Liss, Inc. [source] Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell lineINTERNATIONAL JOURNAL OF CANCER, Issue 7 2008Akihiro Naito Abstract Although the net benefits of tamoxifen in adjuvant breast cancer therapy have been proven, the recurrence of the cancer in an aggressive and hormone independent form has been highly problematic. We previously demonstrated the important role mitochondrial DNA (mtDNA) plays in hormone-independence in prostate cancer. Here, the role of mtDNA in breast cancer progression was investigated. We established hydroxytamoxifen (4-OHT) resistant HTRMCF by growing MCF-7, human breast adenocarcinoma cells, in the presence of 4-OHT. HTRMCF was cross-resistant to 4-OHT and ICI182,780 concurrent with the depletion of mtDNA. To further investigate the role of mtDNA depletion, MCF-7 was depleted of mtDNA by treatment with ethidium bromide. MCF,0 was resistant to both 4-OHT and ICI182,780. Furthermore, cybrid (MCFcyb) prepared by fusion MCF,0 with platelet to transfer mtDNA showed susceptibility to antiestrogen. Surprisingly, after withdrawal of 4-OHT for 8 weeks, HTRMCF and their clones became susceptible to both drugs concurrent with a recovery of mtDNA. Herein, our results substantiated the first evidence that the depletion of mtDNA induced by hormone therapy triggers a shift to acquired resistance to hormone therapy in breast cancer. In addition, we showed that mtDNA depletion can be reversed, rendering the cancer cells susceptible to antiestrogen. The fact that the hormone independent phenotype can be reversed should be a step toward more effective treatments for estrogen-responsive breast cancer. © 2007 Wiley-Liss, Inc. [source] Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell lineINTERNATIONAL JOURNAL OF CANCER, Issue 2 2008Massimiliano Cariati Abstract The identification of mammary epithelial stem cells raises the hypothesis that these cells may be crucial in the pathogenesis of breast cancer. To further support this, a highly tumourigenic sub-population of cancer cells has recently been identified in primary and metastatic breast cancer samples. In this study, a sub-population of cells displaying features normally attributed to stem cells was identified within the breast cancer cell line MCF-7. This sub-population is capable of growth in anchorage-independent conditions as spherical organoids, displays resistance to proapoptotic agents and significantly greater tumourigenicity than its parental line, with as few as 1,000 cells able to form tumours in immunodeficient mice. Cells within this sub-population can be enriched by serial passages in anchorage-independence, and are characterized by over-expression of the adhesion molecule ,6-integrin. Alpha-6 integrin proves to be required for the growth and survival of these cells, as the knockdown of ITGA6 causes mammosphere-derived cells to lose their ability to grow as mammospheres and abrogates their tumourigenicity in mice. These findings support the existence of a highly tumourigenic sub-population in breast cancer cells. Furthermore, it shows ,6-integrin as a potential therapeutic target aimed at tumour-generating subsets of breast cancer cells. © 2007 Wiley-Liss, Inc. [source] BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHRINTERNATIONAL JOURNAL OF CANCER, Issue 1 2007Lu Hao Abstract Cyclin D1 plays an important role in cell cycle progression. In breast cancer, Cyclin D1 expression is deregulated by several mechanisms. We previously showed that in breast cancer cells, overexpression of BRCA1-IRIS induces Cyclin D1 overexpression and increases cell proliferation. BRCA1-IRIS alone or in complex with steroid receptor co-activators was targeted to the cyclin D1 promoter pre-bound by the c-Jun/AP1 and activated its transcription, which could explain the co-overexpression of BRCA1-IRIS and Cyclin D1 in breast cancer cells coupled with their increased proliferation. We report here an alternate or a complementary pathway by which BRCA1-IRIS activates Cyclin D1 expression. BRCA1-IRIS overexpression decreases the expression of the dual specificity phosphatase, DUSP3/VHR, an endogenous inhibitor of several MAPKs, including c-Jun N-terminal kinase. Although, the mechanism by which BRCA1-IRIS overexpression accomplishes that is not yet known, it is sufficient to induce Cyclin D1 overexpression in a human mammary epithelial cell model. Cyclin D1 overexpression could be blocked by co-overexpression of VHR in those cells. Furthermore, in 2 breast cancer cell lines that overexpress both BRCA1-IRIS and Cyclin D1 (MCF-7 and SKBR3) depletion of BRCA1-IRIS by RNA interference attenuated the expression of Cyclin D1 by elevating the expression level of VHR. These data demonstrate a critical role for BRCA1-IRIS in human breast cancer cell-cycle control and suggest that deregulated expression of BRCA1-IRIS is likely to reduce dependence on normal physiological growth stimuli, thereby providing a growth advantage to tumor cells and a potential mechanism of resistance to endocrine therapy. © 2007 Wiley-Liss, Inc. [source] Reversal of doxorubicin resistance in breast cancer cells by photochemical internalizationINTERNATIONAL JOURNAL OF CANCER, Issue 11 2006Pei-Jen Lou Abstract Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site-specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF-7 and MCF-7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS2a (disulfonated meso-tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC50 (drug concentration for 50% reduction in colony formation) was 0.1 ,M for MCF-7 and 1 ,M for MCF-7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC50 concentration was 0.1 ,M for both cell lines. Comparable changes were seen with assay of cell viability using 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF-7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF-7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endo-lysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR. © 2006 Wiley-Liss, Inc. [source] Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Rajendra Kumari Abstract Parathyroid-hormone related protein (PTHrP) is the primary factor in humoral hypercalcemia of malignancy and is highly secreted by breast cancers. The pro-hormone undergoes post-translational processing and cleavage to give rise to mature secretory peptides, one of which is midregion PTHrP (38-94/95/101) containing a nuclear localisation sequence (NLS) in amino acids (87-106). The current study investigates whether the NLS in midregion PTHrP is important in breast cancer growth. PTHrP-(67-101), a midregion PTHrP fragment containing NLS-(87-101) significantly increased growth of MCF-7 and MDA-MB231 cells (126.3 and 121.3% of control respectively in serum conditions), independent of PTHR1 whereas PTHrP-(67-86), which lacks the NLS did not. Fluorescent-labelled PTHrP-(67-101) translocated to the nucleus, whereas PTHrP-(67-86) remained cytosolic and a scrambled(+NLS) peptide was not internalised. In comparison, no growth influence or uptake was seen in non-tumour breast cells (Hs578Bst). Increases in intracellular calcium mobilisation were observed in breast cancer cells stimulated with both PTHrP-(67-101) and PTHrP-(67-86) (EC50 of 3.2 pM and 2.2 pM respectively for MCF-7 cells), whereas inositide turnover was not detected. Both nuclear uptake and calcium signalling were attenuated in the presence of EGTA, but not with U73122 or N-terminal PTHrP peptides. Our studies indicate that the NLS-containing midregion PTHrP peptide is dependent on both internalisation and nuclear translocation to induce growth in breast cancer cells. These findings highlight the importance of midregion PTHrP and its receptor in breast cancer growth and may provide potential targets for future therapeutic intervention. © 2006 Wiley-Liss, Inc. [source] A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenograftsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2005Liliane Goetsch Abstract Interaction of insulin-like growth factor receptor I (IGF-IR) with its ligands has been reported to induce cell proliferation, transformation and blockade of cell apoptotic functions. IGF-IR is overexpressed on numerous tumor cell types and its blockade could be of importance for anti-cancer therapy. We have generated a humanized anti-IGF-IR antibody h7C10 that blocks in vitro IGF-I and IGF-II-induced cell proliferation of MCF-7 breast cancer cells. Analysis of the IGF-I transduction cascade demonstrated that the humanized anti-IGF-IR antibody and its murine parental form block IGF-I-induced tyrosine phosphorylation, both its ,-chain and IRS-1 tyrosine phosphorylation. This presumably leads to cell cycle arrest and, consequently, growth inhibition. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, or its murine parental form 7C10, inhibited significantly tumor growth. An almost complete inhibition of A549 tumor growth was observed when mice were treated with the anti-IGF-IR antibody combined with either a chemotherapeutic agent, Vinorelbine or an anti-epidermal growth factor receptor (EGFR) antibody, 225. Combined therapy prolonged significantly the life span of mice in an orthotopic in vivo model of A549; the combination of the anti-IGF-IR antibody with an anti-EGFR antibody was superior to the Vinorelbine combination. The present results indicate that the humanized anti-IGF-IR antibody h7C10 has a great potential for cancer therapy when combined with either a chemotherapeutic agent or an antibody that targets other growth factor receptors, such as the epidermal growth factor receptor. [source] Nutritional channels in breast cancerJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 9b 2009Alejandro Godoy Abstract Breast cancers increase glucose uptake by increasing expression of the facilitative glucose transporters (GLUTs), mainly GLUT1. However, little is known about the relationship between GLUT1 expression and malignant potential in breast cancer. In this study, expression and subcellular localization of GLUT1 was analysed in vivo in breast cancer tissue specimens with differing malignant potential, based on the Scarff-Bloom-Richardson (SBRI, II, III) histological grading system, and in vitro in the breast cancer cell lines, MDA-MB-468 and MCF-7, and in MDA-MB-468 cells grown as xenografts in nude athymic BALB/c male mice. In situ hybridization analyses demonstrated similar levels of GLUT1 mRNA expression in tissue sections from breast cancers of all histological grades. However, GLUT1 protein was expressed at higher levels in grade SBRII cancer, compared with SBRI and SBRIII, and associated with the expression of the proliferation marker PCNA. Immunolocalization analyses in SBRII cancers demonstrated a preferential localization of GLUT1 to the portions of the cellular membrane that faced neighbouring cells and formed ,canaliculi-like structures', that we hypothesize could have a potential role as ,nutritional channels'. A similar pattern of GLUT1 localization was observed in confluent cultures of MDA-MB-468 and MCF-7, and in MDA-MB-468 cells grown as xenografts, but not in the normal breast epithelial cell line HMEC. However, no relationship between GLUT1 expression and malignant potential of human breast cancer was observed. Preferential subcellular localization of GLUT1 could represent a physiological adaptation of a subset of breast cancer cells that form infiltrative tumours with a nodular growth pattern and that therefore need a major diffusion of glucose from blood vessels. [source] High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic abilityJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Alysha K. Croker Abstract Cancer stem cells (CSCs) have recently been identified in leukaemia and solid tumours; however, the role of CSCs in metastasis remains poorly understood. This dearth of knowledge about CSCs and metastasis is due largely to technical challenges associated with the use of primary human cancer cells in pre-clinical models of metastasis. Therefore, the objective of this study was to develop suitable pre-clinical model systems for studying stem-like cells in breast cancer metastasis, and to test the hypothesis that stem-like cells play a key role in metastatic behaviour. We assessed four different human breast cancer cell lines (MDA-MB-435, MDA-MB-231, MDA-MB-468, MCF-7) for expression of prospective CSC markers CD44/CD24 and CD133, and for functional activity of aldehyde dehydrogenase (ALDH), an enzyme involved in stem cell self-protection. We then used fluorescence-activated cell sorting and functional assays to characterize differences in malignant/metastatic behaviour in vitro (proliferation, colony-forming ability, adhesion, migration, invasion) and in vivo (tumorigenicity and metastasis). Sub-populations of cells demonstrating stem-cell-like characteristics (high expression of CSC markers and/or high ALDH) were identified in all cell lines except MCF-7. When isolated and compared to ALDHlowCD44low/, cells, ALDHhiCD44+CD24, (MDA-MB-231) and ALDHhiCD44+CD133+ (MDA-MB-468) cells demonstrated increased growth (P < 0.05), colony formation (P < 0.05), adhesion (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). Furthermore, following tail vein or mammary fat pad injection of NOD/SCID/IL2, receptor null mice, ALDHhiCD44+CD24, and ALDHhiCD44+CD133+ cells showed enhanced tumorigenicity and metastasis relative to ALDHlowCD44low/, cells (P < 0.05). These novel results suggest that stem-like ALDHhiCD44+CD24, and ALDHhiCD44+CD133+ cells may be important mediators of breast cancer metastasis. [source] ,4 phosphoprotein interacts with EDD E3 ubiquitin ligase and poly(A)-binding proteinJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2010William J. McDonald Abstract Mammalian ,4 phosphoprotein, the homolog of yeast Tap42, is a component of the mammalian target-of-rapamycin (mTOR) pathway that regulates ribogenesis, the initiation of translation, and cell-cycle progression. ,4 is known to interact with the catalytic subunit of protein phosphatase 2A (PP2Ac) and to regulate PP2A activity. Using ,4 as bait in yeast two-hybrid screening of a human K562 erythroleukemia cDNA library, EDD (E3 isolated by differential display) E3 ubiquitin ligase was identified as a new protein partner of ,4. EDD is the mammalian ortholog of Drosophila hyperplastic discs gene (hyd) that controls cell proliferation during development. The EDD protein contains a PABC domain that is present in poly(A)-binding protein (PABP), suggesting that PABP may also interact with ,4. PABP recruits translation factors to the poly(A)-tails of mRNAs. In the present study, immunoprecipitation/immunoblotting (IP/IB) analyses showed a physical interaction between ,4 and EDD in rat Nb2 T-lymphoma and human MCF-7 breast cancer cell lines. ,4 also interacted with PABP in Nb2, MCF-7 and the human Jurkat T-leukemic and K562 myeloma cell lines. COS-1 cells, transfected with Flag-tagged-pSG5-EDD, gave a (Flag)-EDD,,4 immunocomplex. Furthermore, deletion mutants of ,4 were constructed to determine the binding site for EDD. IP/IB analysis showed that EDD bound to the C-terminal region of ,4, independent of the ,4-PP2Ac binding site. Therefore, in addition to PP2Ac, ,4 interacts with EDD and PABP, suggesting its involvement in multiple steps in the mTOR pathway that leads to translation initiation and cell-cycle progression. J. Cell. Biochem. 110: 1123,1129, 2010. Published 2010 Wiley-Liss, Inc. [source] Down-regulation of uPA and uPAR by 3,3,-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2009Aamir Ahmad Abstract 3,3,-Diindolylmethane (DIM) is a known anti-tumor agent against breast and other cancers; however, its exact mechanism of action remains unclear. The urokinase plasminogen activator (uPA) and its receptor (uPAR) system are involved in the degradation of basement membrane and extracellular matrix, leading to tumor cell invasion and metastasis. Since uPA-uPAR system is highly activated in aggressive breast cancer, we hypothesized that the biological activity of B-DIM could be mediated via inactivation of uPA-uPAR system. We found that B-DIM treatment as well as silencing of uPA-uPAR led to the inhibition of cell growth and motility of MDA-MB-231 cells, which was in part due to inhibition of VEGF and MMP-9. Moreover, silencing of uPA-uPAR led to decreased sensitivity of these cells to B-DIM indicating an important role of uPA-uPAR in B-DIM-mediated inhibition of cell growth and migration. We also found similar effects of B-DIM on MCF-7, cells expressing low levels of uPA-uPAR, which was due to direct down-regulation of MMP-9 and VEGF, independent of uPA-uPAR system. Interestingly, over-expression of uPA-uPAR in MCF-7 cells attenuated the inhibitory effects of B-DIM. Our results, therefore, suggest that B-DIM down-regulates uPA-uPAR in aggressive breast cancers but in the absence of uPA-uPAR, B-DIM can directly inhibit VEGF and MMP-9 leading to the inhibition of cell growth and migration of breast cancer cells. J. Cell. Biochem. 108: 916,925, 2009. © 2009 Wiley-Liss, Inc. [source] Differential regulation of protein expression, growth and apoptosis by natural and synthetic retinoidsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2003M.A. Christine Pratt Abstract All- trans retinoic acid (ATRA) can down regulate the anti-apoptotic protein Bcl-2 and the cell cycle proteins cyclin D1 and cdk2 in estrogen receptor-positive breast cancer cells. We show here that retinoids can also reduce expression of the inhibitor of apoptosis protein, survivin. Here we have compared the regulation of these proteins in MCF-7 and ZR-75 breast cancer cells by natural and synthetic retinoids selective for the RA receptors (RARs) ,, ,, and , then correlated these with growth inhibition, induction of apoptosis and chemosensitization to Taxol. In both cell lines ATRA and 9- cis RA induced the most profound decreases in cyclin D1 and cdk2 expression and also mediated the largest growth inhibition. The RAR, agonist, Ro 40-6055 also strongly downregulated these proteins although did not produce an equivalent decrease in S-phase cells. Only ATRA induced RAR, expression. ATRA, 9- cis RA and 4-HPR initiated the highest level of apoptosis as determined by mitochondrial Bax translocation, while only ATRA and 9- cis RA strongly reduced Bcl-2 and survivin protein expression. Enumeration of dead cells over 96 h correlated well with downregulation of both survivin and Bcl-2. Simultaneous retinoid-mediated reduction of both these proteins also predicted optimal Taxol sensitization. 4-HPR was much weaker than the natural retinoids with respect to Taxol sensitization, consistent with the proposed requirement for reduced Bcl-2 in this synergy. Neither the extent of cell cycle protein regulation nor AP-1 inhibition fully predicted the antiproliferative effect of the synthetic retinoids suggesting that growth inhibition requires regulation of a spectrum of RAR-regulated gene products in addition even to pivotal cell cycle proteins. © 2003 Wiley-Liss, Inc. [source] Retinoic acid induces expression of the interleukin-1, gene in cultured normal human mammary epithelial cells and in human breast carcinoma linesJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2002Limin Liu Retinoic acid (RA) and its derivatives inhibit the proliferation of normal human mammary epithelial cells (HMEC) and some breast carcinoma lines by mechanisms which are not fully understood. To identify genes that mediate RA-induced cell growth arrest, an HMEC cDNA library was synthesized and subtractive screening was performed. We identified the interleukin-1, (IL-1,) gene as an RA induced gene in HMEC. Northern blot analyses showed that the IL-1, gene was up-regulated as early as 2 h after RA treatment. Results from the treatment of HMEC with cycloheximide and actinomycin D indicated that the regulation of the IL-1, gene by RA occurred at the transcriptional level and that the IL-1, gene is a direct, downstream target gene of RA. To evaluate the effects of IL-1, on cell proliferation, the proliferation of HMEC was measured in the presence of RA or IL-1,, or both. Either RA or IL-1, could significantly inhibit the proliferation of HMEC. However, the addition of soluble IL-1 receptor antagonist (sIL-1ra) to the cell culture medium did not block RA-induced HMEC growth inhibition, whereas sIL-1ra did block the growth inhibition of HMEC by IL-1,. IL-1, expression was not observed in the three carcinoma cell lines, MCF-7, MDA-MB-231, and MDA-MB-468, as compared to the HMEC. Growth curves of the breast carcinoma cell lines showed strong inhibitory effects of RA and IL-1, on the growth of the estrogen receptor (ER) positive MCF-7 cell line, but only a small effect on the ER negative MDA-MB-231 cells. The expression of the IL-1, gene was also transcriptionally activated by RA in normal epithelial cells of prostate and oral cavity. Our results suggest that: (a) the IL-1, gene is a primary target of RA receptors in HMEC; (b) the enhanced expression of the IL-1, gene does not mediate the RA-induced growth arrest of HMEC; and (c) the expression of the IL-1, gene is low or absent in all three human breast carcinoma cell lines examined, but the defect in the IL-1, signaling pathway may be different in ER positive versus ER negative carcinoma cells. © 2002 Wiley-Liss, Inc. [source] Distribution and binding of novel photosensitizer 2-devinyl-2-(1-methoxyl-ethyl) chlorin f in human breast cancer cells MCF-7LASER PHYSICS LETTERS, Issue 6 2009Y. Liu Abstract The interaction of novel Photosensitizer 2-devinyl-2-(1-methoxyl-ethyl) chlorin f (CPD4) with human breast cancer cells MCF-7 was studied by fluorescence spectrum and laser confocal scan microscopy (LCSM). The experimental results exhibit that fluorescence emission band of CPD4 in MCF-7 cells move to long wavelength about 5 nm compared with that in incubation solution, which suggest that CPD4 could enter into MCF-7 cells and bind them strongly by electrostatic or hydrogen binding interaction. The LCSM images of CPD4 in MCF-7 cells show that the binding of CPD4 in MCF-7 cells takes place in cellular membrane and mitochondria mainly. These results indicate that CPD4 can be of selective subcellular location, but not free ionic status in MCF-7 cells.CPD4 could be a kind of promising photosensitizer for Photodynamic therapy. (© 2009 by Astro Ltd., Published exclusively by WILEY-VCH Verlag GmbH & Co. KGaA) [source] Cisplatin resistance conferred by the RAD51D (E233G) genetic variant is dependent upon p53 status in human breast carcinoma cell linesMOLECULAR CARCINOGENESIS, Issue 7 2009Aditi Nadkarni Abstract RAD51D, a paralog of the mammalian RAD51 gene, contributes towards maintaining genomic integrity by homologous recombination DNA repair and telomere maintenance. A RAD51D variant, E233G, was initially identified as a potential susceptibility allele in high-risk, site-specific, familial breast cancer. We describe in this report that the Rad51d (E233G) genetic variant confers increased cisplatin resistance and cell growth phenotypes in human breast carcinoma cell lines with a mutant p53 gene (BT20 and T47D) but not with a wild-type p53 gene (MCF-7). Treatment with a p53 specific inhibitor, pifithrin ,, restored this resistant phenotype in the MCF-7 cell line. Additionally, Rad51d (E233G) conferred increased cisplatin resistance of an MCF7 cell line in which p53 expression was stably knocked down by shRNAp53, indicating that the effect of this variant is dependent upon p53 status. Further study of Rad51d (E233G) will provide mechanistic insight towards the role of RAD51D in cellular response to anticancer agents and as a potential target for cancer therapy. © 2009 Wiley-Liss, Inc. [source] Phytochemicals in olive-leaf extracts and their antiproliferative activity against cancer and endothelial cellsMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 5 2009Vlassios Goulas Abstract Olive oil compounds is a dynamic research area because Mediterranean diet has been shown to protect against cardiovascular disease and cancer. Olive leaves, an easily available natural material of low cost, share possibly a similar wealth of health benefiting bioactive phytochemicals. In this work, we investigated the antioxidant potency and antiproliferative activity against cancer and endothelial cells of water and methanol olive leaves extracts and analyzed their content in phytochemicals using LC-MS and LC-UV-SPE-NMR hyphenated techniques. Olive-leaf crude extracts were found to inhibit cell proliferation of human breast adenocarcinoma (MCF-7), human urinary bladder carcinoma (T-24) and bovine brain capillary endothelial (BBCE). The dominant compound of the extracts was oleuropein; phenols and flavonoids were also identified. These phytochemicals demonstrated strong antioxidant potency and inhibited cancer and endothelial cell proliferation at low micromolar concentrations, which is significant considering their high abundance in fruits and vegetables. The antiproliferative activity of crude extracts and phytochemicals against the cell lines used in this study is demonstrated for the first time. [source] 1H MRS studies of signals from mobile lipids and from lipid metabolites: comparison of the behavior in cultured tumor cells and in spheroidsNMR IN BIOMEDICINE, Issue 2 2004Antonella Rosi Abstract 1H magnetic resonance studies on MCF-7 and HeLa cells were undertaken to reveal differences in lipid and lipid metabolite signals during the growth in culture. High intensity mobile lipid (ML) signals were found during the first days in culture, while afterwards the same signals declined and started increasing again at confluence and at late confluence. At the same time, signals from the lipid metabolite phosphocholine decreased in intensity while signals from glycerophosphocholine in MCF-7 and from choline in HeLa increased as cells approached confluence. Spectral parameters from actively proliferating and non-proliferating cells were used to classify cells with respect to the proliferative conditions by means of a multivariate statistical analysis. Furthermore, it was shown that polyunsaturation of mobile lipid chains was lower in the confluent group with respect to the actively proliferating cells. The examination of spectra from suspensions of MCF-7 spheroids with diameter smaller than 500,,m suggests that cells in spheroids are in condition of lipid metabolism similar to that of confluent cultured cells. Copyright © 2004 John Wiley & Sons, Ltd. [source] Antimicrobial and cytotoxic activities of Malaysian endophytesPHYTOTHERAPY RESEARCH, Issue 5 2010Kalavathy Ramasamy Abstract Endophytes, which are receiving increasing attention, have been found to be potential sources of bioactive metabolites following the discovery of paclitaxel producing endophytic fungi. In the present study, a total of 348 endophytes were isolated from different parts of 24 Malaysian medicinal plants. Three selected endophytes (HAB10R12, HAB11R3 and HAB21F25) were investigated for their antimicrobial and cytotoxic activities. For antimicrobial activity, HAB10R12 and HAB11R3 were found to be most active against bacteria and fungi, respectively. Their antimicrobial effects were comparable to, if not better than, a number of current commercial antibacterial and antifungal agents. Both HAB10R12 and HAB21F25 were found to be potential anticancer drug candidates, having potent activity against MCF-7 and HCT116 cell lines and warrant further investigation. Copyright © 2009 John Wiley & Sons, Ltd. [source] Withanolide sulfoxide from Aswagandha roots inhibits nuclear transcription factor-kappa-B, cyclooxygenase and tumor cell proliferationPHYTOTHERAPY RESEARCH, Issue 7 2009Vanisree Mulabagal Abstract Investigation of the methanol extract of Aswagandha (Withania somnifera) roots for bioactive constituents yielded a novel withanolide sulfoxide compound (1) along with a known withanolide dimer ashwagandhanolide (2) with an S-linkage. The structure of compound 1 was established by extensive NMR and MS experiments. Compound 1 was highly selective in inhibiting cyclooxygenase-2 (COX-2) enzyme by 60% at 100 µm with no activity against COX-1 enzyme. The IC50 values of compound 1 against human gastric (AGS), breast (MCF-7), central nervous system (SF-268) and colon (HCT-116) cancer cell lines were in the range 0.74,3.63 µm. Both S-containing dimeric withanolides, 1 and 2, completely suppressed TNF-induced NF- ,B activation when tested at 100 µm. The isolation of a withanolide sulfoxide from W. somnifera roots and its ability to inhibit COX-2 enzyme and to suppress human tumor cell proliferation are reported here for the first time. In addition, this is the first report on the abrogation of TNF-induced NF- ,B activation for compounds 1 and 2. Copyright © 2009 John Wiley & Sons, Ltd. [source] Antiproliferative effect of flavonoids and sesquiterpenoids from Achillea millefolium s.l. on cultured human tumour cell linesPHYTOTHERAPY RESEARCH, Issue 5 2009Boglárka Csupor-Löffler Abstract The antiproliferative activities of n -hexane, chloroform, aqueous-methanol and aqueous extracts of the aerial parts of the Achillea millefolium aggregate on three human tumour cell lines were investigated by means of MTT assays. The chloroform-soluble extract exerted high tumour cell proliferation inhibitory activities on HeLa and MCF-7 cells, and a moderate effect on A431 cells; accordingly, it was subjected to detailed bioactivity-guided fractionation. As a result of the multistep chromatographic purifications (VLC, CPC, PLC, gel filtration), five flavonoids (apigenin, luteolin, centaureidin, casticin and artemetin) and five sesquiterpenoids (paulitin, isopaulitin, psilostachyin C, desacetylmatricarin and sintenin) were isolated and identified by spectroscopic methods. The antiproliferative assay demonstrated that centaureidin is the most effective constituent of the aerial parts of yarrow: high cell growth inhibitory activities were observed especially on HeLa (IC50 0.0819 µm) and MCF-7 (IC50 0.1250 µm) cells. Casticin and paulitin were also highly effective against all three tumour cell lines (IC50 1.286,4.76 µm), while apigenin, luteolin and isopaulitin proved to be moderately active (IC50 6.95,32.88 µm). Artemetin, psilostachyin C, desacetylmatricarin and sintenin did not display antiproliferative effects against these cell lines. This is the first report on the occurrence of seco -pseudoguaianolides (paulitin, isopaulitin and psilostachyin C) in the Achillea genus. Copyright © 2008 John Wiley & Sons, Ltd. [source] Chemical composition and antiproliferative activity of essential oil from the leaves of a medicinal herb, Schefflera heptaphyllaPHYTOTHERAPY RESEARCH, Issue 1 2009Yao-Lan Li Abstract Schefflera heptaphylla (L.) Frodin is a medicinal herb widely used as a main ingredient of the popular health tea formulation against infections in Southern China. Twenty-seven volatile compounds were identified by GC-MS analysis from the essential oil obtained from the leaves of S. heptaphylla, and 17 of them belonged to monoterpenes or sesquiterpenes. The main volatile constituent in S. heptaphylla was found to be a monoterpene, , -pinene, comprising about 22% of the total volatile components. The essential oil showed significant antiproliferative activity against three cancer cell lines, MCF-7, A375 and HepG2 cells, with IC50 values of 7.3 µg/mL, 7.5 µg/mL and 6.9 µg/mL, respectively. The result of the cytotoxicity assay indicates that (,)- , -pinene and (+)- , -pinene (commercially available from Sigma) also possessed antiproliferative activity against the cancer cells MCF-7, A375 and HepG2 with IC50 values ranging from 147.1 to 264.7 µm. Copyright © 2008 John Wiley & Sons, Ltd. 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